In this research project, we have investigated how modification of macrophages rather than modification of LDL affects macrophage metabolism of native LDL. We have learned that macrophage cholesterol accumulation can occur with native LDL when macrophages are differentiated from monocytes with the specific growth factor, M-CSF. M-CSF differentiated macrophages show constitutive uptake and degradation of native LDL. LDL uptake does not depend on macrophage oxidation of LDL or macrophage binding of LDL. Rather, the M-CSF differentiated macrophages take up LDL by constitutive macropinocytosis, a process by which macrophages and some other cell types take up large amounts of fluid. The macrophages take up LDL as part of the fluid that they ingest during macropinocytosis. This produces cholesterol accumulation in macrophages to levels characteristic of macrophage foam cells in atherosclerotic plaques. This novel mechanism of macrophage cholesterol accumulation shows that oxidative modification of LDL is not necessary for foam cell formation to occur.[unreadable] [unreadable] In related research, we have identified two distinct macrophage lineages within human coronary atherosclerotic lesions. These lineages correspond to distinct macrophage phenotypes that can be generated in vitro when human monocytes are differentiated with either GM-CSF or M-CSF. Both macrophage phenotypes are present within the human coronary artery and accumulate lipid within coronary artery atherosclerotic plaques. However, the M-CSF macrophage phenotype predominates within plaques, while the GM-CSF phenotype predominates within normal coronary artery. Thus, the M-CSF macrophage phenotype, which shows constitutive macropinocytosis of LDL and is associated with inflammation in other tissues, may be an important atherogenic macrophage lineage that promotes the development of atherosclerotic plaques.[unreadable] [unreadable] Liver X receptors (LXRs) are ligand-activated transcription factors involved in the control of lipid metabolism and inflammation. Several studies have recently shown that LXRs inhibit atherosclerosis development in animals. It is currently believed that the mechanism by which LXRs inhibit atherosclerosis is by promoting macrophage cholesterol efflux via induction of the cholesterol efflux genes ABCA1 and ABCG1 in macrophages. We investigated whether LXRs affect macrophage uptake of LDL and cholesterol accumulation in the M-CSF differentiated macrophages. We learned that differentiation of macrophages in the presence of LXR agonists greatly decreases macrophage macropinocytosis of LDL and as a result decreases macrophage cholesterol accumulation. These findings reveal a novel mechanism by which LXR agonists may inhibit cholesterol accumulation and atherosclerosis, namely by inhibiting macrophage uptake of LDL in plaques.[unreadable] [unreadable] In conclusion, our findings show that macropinocytosis of LDL is a plausible mechanism that can explain how macrophages accumulate cholesterol and become disease-causing foam cells. The findings direct attention to macrophage macropinocytosis as a relevant pathway to target for modulating macrophage cholesterol accumulation in atherosclerosis. Our current research is directed at identifying drugs that inhibit macrophage macropinocytosis of LDL.